Examining the effects of myeloperoxidase modulation and deficiency in murine models of experimental colitis and colitis-associated cancer

Abstract

Inflammatory bowel disease (IBD) is a chronic, debilitating condition and a risk factor for colitis-associated colorectal cancer (CAC) development. Manifesting as Crohn’s disease or ulcerative colitis, IBD is characterised by chronic, uncontrolled inflammation and leukocytic infiltration into the intestinal mucosa. The microbicide myeloperoxidase (MPO) produces excess HOCl during inflammation, causing irreversible host tissue damage and exacerbating disease severity. Previous research has shown alleviation of dextran sodium sulfate (DSS) acute colitis by the nitroxide 4-methoxy-tempo, likely through MPO inhibition. Yet, limited studies have investigated potential therapeutic effects of MPO inhibition in chronic inflammatory intestinal disorders. While host immunity is significant in IBD aetiology, pathogenesis is multifactorial, with gut dysbiosis also implicated in disease inception, progression and outcome. Thus, studies herein aimed to investigate effects of MPO inhibition via the nitroxide 4-hydroxy-tempo (TEMPOL) and separately via MPO-/- mice within chronic murine models of DSS colitis and DSS/azoxymethane (AOM) CAC, to characterise MPO-/- faecal microbiome and to determine effects of faecal microbiota normalisation in acute disease progression and outcome. Findings here reveal TEMPOL attenuated acute DSS colitis in Wt mice while MPO-/- mice saw no protection from disease. Moreover, neither MPO-/- mice or TEMPOL ameliorated chronic DSS colitis and DSS/AOM CAC. Outcomes from faecal microbiome studies between Wt and MPO-/- mice showed a marked difference in bacterial populations between genotypes and within the same genotype at different timepoints. These findings may have important implications on disease phenotype in MPO-/- mice, in interpreting models where gene deficient mice with microbicidal deficiencies are employed to infer a role in disease pathogenesis and in needing to adopt microbiota normalisation protocols to reduce effects from unknown variables.